Sle1 on murine chromosome 1 and Sle3 on murine chromosome 7 represent 2 of the strongest loci for lupus in the NZM2410 mouse model. To understand how these loci contribute to lupus, these disease loci have been backcrossed onto the relatively normal C57BL/6 background as congenic intervals. Whereas B6 mice are healthy, B6.Sle1 mice develop mild lupus, and B6.Sle1.Sle3 bicongenic mice develop severe lupus nephritis. We have recently documented that mature B-cells in these congenics exhibit progressive activation of multiple signaling pathways, including the AKT/mTOR axis, various MAPK pathways, NFkB, STAT3, STAT5, and various Bcl-2 family members, with the levels of activation correlating well with disease severity and susceptibility gene dosage. Importantly, the activation of some of these axes, notably NFkB and STAT3, were particularly pronounced in bicongenic mice with severe lupus, but not in B6.Sle1 mice. Whether the activation of any of these signaling pathways is necessary or sufficient for disease is not known. We hypothesize that NFkB and STAT3 activation is essential for the pathogenesis of lupus. This will be tested using a genetic approach in Aim 2 and a pharmacological approach in Aim 3. Though the culprit gene for Sle3 remains unknown, we have learned that the candidate gene for the strongest sub-locus within Sle1, namely SLAMF6/Ly108, functions in a B-cell intrinsic fashion to breach early B-cell tolerance. Presently, the molecular mechanisms through which Ly108 might breach tolerance remain unclear. We hypothesize that polymorphic variants of Ly108 may breach B- cell tolerance by engaging different signaling pathways within immature B-cells. This hypothesis will be tested in Aim 1. Collectively, these studies have important implications towards the mechanistic origins o systemi lupus erythematosus and how it is managed therapeutically. PUBLIC HEALTH RELEVANCE: We do not have a clear understanding of which signaling pathways within cells are most activated in different stages of lupus. Using novel genetically simplified mouse models, the proposed study aims to define the precise molecular contributions of different cell types in lupus. These studies will also ascertain if 2 particular molecules activated in lupus lymphocytes are essential for disease. Uncovering essential nodes in lupus pathogenesis using these novel genetic models are likely to pave the way towards more effective therapy in lupus targeting critical signaling nodes.